PROJECT SUMMARY Aging is accompanied by a decrease in cognitive ability, which can progress into cognitive impairment and dementia. Cannabinoid receptors, the molecular target of ?9-THC in marijuana, modulate long- and short-term synaptic plasticity at many central synapses. In young mice and rats, pharmacological activation of these receptors impairs memory, whereas blockade exerts pro-cognitive effects. The opposite occurs, however, in aged animals, in which cannabinoid receptor activation alleviates, whereas genetic cannabinoid receptor deletion enhances, aging-related cognitive deficits. Several possible mechanisms have been proposed to explain how cannabinoid receptor signaling might differentially influence cognitive function in young and old animals, but very limited data are available about the role played by endocannabinoid ligands such as 2- arachidonoyl-sn-glycerol (2-AG) and anandamide. In preliminary studies, we found that 2-AG production is impaired in the hippocampus of 18- and 21-month old mice, compared to 12-month old mice. Based on this finding, we hypothesize that age-dependent reductions in 2-AG mobilization (formation and/or deactivation) contribute to cognitive aging. We have two Specific Aims that are relevant to a test of this hypothesis. Aim 1. Effects of reduced forebrain 2-AG mobilization on cognitive aging. We have generated mice that overexpress the 2-AG-hydrolyzing enzyme, monoacylglycerol lipase (MGL), in excitatory neurons of the forebrain (MGL-tg mice). This genetic manipulation reduces forebrain 2-AG levels without altering expression of cannabinoid receptors or endocannabinoid-related proteins and lipids. This model is unique in that it does not display the compensatory changes seen in knock-out mouse models that lack the ability to produce or degrade 2-AG. Using MGL-tg mice, we will ask whether forebrain 2-AG signaling is involved in cognitive aging. We will compare MGL-tg and wild-type mice ? aged 2 , 5, 12 and 18 months ? for three key parameters: Study 1.1. Forebrain 2-AG signaling; Study 1.2. Cognitive performance; and, Study 1.3. Markers of neural inflammation. Aim 2. Effects of enhanced forebrain 2-AG mobilization on cognitive aging. If decreased 2-AG signaling contributes to cognitive aging, then pharmacological correction of this deficit should ameliorate cognition in old animals. We will determine whether subchronic oral administration of the compound NF1819, a novel MGL inhibitor with favorable drug-like properties, improves age-related cognitive deficits in MGL-tg and wild-type mice. In a first experiment (Study 2.1), we will determine the optimal dosing of NF1819, and in a subsequent experiment (Study 2.2), we will administer NF1819 for 30 days or 90 days to MGL-tg mice and wild-type controls, testing cognitive performance and neuroinflammatory markers. The project has the potential to uncover new functions of 2-AG signaling in the aging brain, and to lay the groundwork for the discovery of novel strategies to alleviate age-related cognitive deficits.